Inhaled nitric oxide for preterm infants: A systematic review

OBJECTIVE. Our goal was to determine whether, for preterm newborn infants with respiratory disease, inhaled nitric oxide reduced the rates of death, bronchopulmonary dysplasia, intracranial hemorrhage, or neurodevelopmental disability. METHODS. We searched Medline, Embase, Healthstar, and the Cochrane Central Register of Controlled Trials using the search terms "nitric oxide," " clinical trial," and "newborn" and covering 1985-2006. We also searched abstracts of the Pediatric Academic Societies. RESULTS. Eleven randomized, controlled trials of inhaled nitric oxide therapy for preterm infants were found. The trials were grouped into 3 categories according to the entry criteria, that is, entry in the first 3 days of life on the basis of oxygenation criteria ( early rescue), enrollment after 3 days on the basis of elevated risk of bronchopulmonary dysplasia, and routine use for intubated preterm infants. Early rescue treatment based on oxygenation criteria did not seem to affect mortality or bronchopulmonary dysplasia rates. Routine use for intubated preterm infants showed a barely significant reduction in the incidence of the combined outcome of death or bronchopulmonary dysplasia ( relative risk [ RR]: 0.91 [ 95% confidence limits ( CLs): 0.84, 0.99]). Later treatment based on the risk of bronchopulmonary dysplasia showed no significant effect on this outcome. Early rescue treatment showed a trend toward increased incidence of severe intracranial hemorrhage, whereas routine use for intubated preterm infants seemed to show a reduction in the incidence of either severe intracranial hemorrhage or periventricular leukomalacia ( RR: 0.70 [ 95% CLs: 0.53, 0.91]). CONCLUSIONS. Inhaled nitric oxide as rescue therapy for very ill preterm infants undergoing ventilation does not seem to be effective and may increase severe intracranial hemorrhage. Later use of inhaled nitric oxide to prevent bronchopulmonary dysplasia does not seem to be effective. Early routine use of inhaled nitric oxide for mildly sick, preterm infants seems to decrease the risk of serious brain injury and may improve rates of survival without bronchopulmonary dysplasia.